Mar. 6, 2001 Boston, MA (March 6, 2001) -- One of the hallmarks of a cancer cell is its immortality—its ability to divide endlessly. A pair of Harvard Medical School researchers has identified a protein that some 10 percent of tumor cells seem to use to attain their immortal state. By blocking this molecule, it may be possible to stop these cancer cells from proliferating.
The approach might also be used as part of a two-pronged strategy to combat the remaining 90 percent of tumors, the researchers say.
"This gives us a new drug target for cancer," said David Sinclair, HMS assistant professor of pathology. He and Haim Cohen, HMS research fellow in pathology, publish their findings in the March 6 online early edition of the Proceedings of the National Academy of Sciences.
In their early stages, tumor cells can only undergo a limited number of divisions. Eventually, a handful of cells, or possibly only one, breaks through this barrier and gains the power to proliferate without end, ultimately giving rise to a malignant mass.
Most tumor cells become cancerous by turning on a gene for telomerase, a protein that makes the protective caps at each end of a chromosome. These nubs—or telomeres—erode every time a cell divides and it is their steady unraveling that causes a cell to age and die. "The malignant cancer is generally the one that revives its ability to make telomeres," said Sinclair.
But a minority—about 10 percent—of cancer cells manage to rebuild their telomeres without turning on the telomerase gene. Sinclair and his colleagues have evidence that they may be doing this by coopting the WRN protein, which is thought to stabilize telomeres, though not actually build them.
The researchers found that special yeast cells, when deprived of their version of WRN, did not survive beyond the normal number of cell divisions. Yeast cell colonies endowed with their version of WRN, SGS1, were able to proliferate endlessly, presumably because one or a few yeast cells had found a way to break through the barrier.
"In general, we can think of SGS1, and the WRN protein, as longevity molecules," Sinclair said. "Cancer cells may utilize the WRN protein for their own purposes to become immortal and get around the barrier to tumorigenesis and cancer formation."
If WRN plays the same role in the minority of human cancer cells that survive without turning on telomerase, the discovery could lead to a new tumor-fighting strategy. "If we could block or inhibit the WRN protein in these 10 percent of cancers, we'd have a good chance of preventing proliferation," said Sinclair. Indeed, the approach might even be applied to the 90 percent that attain their immortality by switching on the telomerase gene. Researchers have found that when they block the telomerase gene in those cancer cells, some of the cells still manage to preserve telomeres, presumably by switching to the WRN path.
"If you try and tackle the other 90 percent by blocking their telomerase, they'll just jump into the other pathway," Sinclair said. "So we have to have a double-pronged attack."
Nature may have conducted a kind of clinical trial of the anti-WRN strategy. People with a rare disease, Werner's syndrome, are born without the WRN gene. While they age much faster than other people, they do not develop common types of cancers but instead are more likely to develop rarer cancers such as sarcomas (muscle cancers) and meningiomas (brain tumors). "It is possible that the absence of WRN may give them partial protection, which is why these patients don’t develop these other more common cancers. This is pure speculation at the moment," he said.
It is not yet clear how the SGS1 protein—and by implication WRN—is conferring immortality on the cells. Previous work by Sinclair has shown that SGS1 helps to maintain the stability of the chromosome, especially its telomeres.
Because this stability is crucial to the integrity of a cell, one might not want to block WRN in every cell but instead would target an anti-WRN drug only to cancer cells. On the other hand, said Sinclair, Werner's patients don’t begin developing premature aging symptoms until they reach their mid to late teens, which means systemic delivery for short periods—a month or two—may not have deleterious effects.
"What I foresee is either just have a short term dose of this drug or target it to cells that are cancerous," said Sinclair. "Of course, getting this drug to cancer cells is the challenge."
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